Targeted gene sequencing using large panels has become an increasingly important strategy for evaluating disease risk for many inherited diseases. Expanded gene panels are more sensitive than single gene testing and often more cost effective than sequential testing, leading to additional diagnostic and prevention opportunities. However, these panels also identify rare variants of uncertain clinical significance (VUS) in many patients. VUS typically have some characteristics or associated data indicating the variant may be deleterious, but not enough information to definitively classify them as disease causing. It is estimated that hundreds of thousands of such variants are present at low frequencies in the population. The finding of a VUS is problematic for patients and clinicians. Family segregation studies have the potential to yield powerful data to classify variants, but research resources are inadequate to enroll all the families affected by the exploding number of VUS identified in clinical testing. A potential solution to this quandary is to engage patients and their families in performing meaningful segregation analysis to evaluate their own VUS using available online genealogy and social networking tools facilitate identifying and contacting relatives likely to have the same VUS. In this project we will interview patients who have received clinical reports of VUS to explore patient understanding of their VUS, motivation and interest in classification, opinions of barriers and facilitators to talking with family members about VUS, and initial thoughts about potential for providing samples to classify their VUS. We will use input from 15-25 study participants to evaluate and improve an online patient-driven VUS classification toolkit that teaches individuals to better understand their VUS, use available genealogy and networking resources trace how their own variants segregate in their extended family, and potentially participate meaningfully with clinical experts in the classification of their own VUS. We will work with participants to obtain and test DNA from family members, and a molecular genetic pathologist will perform final variant classification. We will interview participants to determine if goals were met and if the toolkit enhanced participant and family understanding of genetic disease risk. We will also interview family members to understand family members perspectives related to privacy, communication, and provision of data or samples for variant classification. The innovative tools to classify VUS that will be developed in this project will meet a growing clinical need. When made broadly available these tools may demonstrate a way to characterize human variants in clinical settings at an unprecedented pace and at a fraction of the current research cost. The data gathered from this initial R21 project will lay the groundwork for additional development of a systematic, family-based method to help patients understand and classify variants of uncertain significance.